Effect modification by statin use status on the association between fine particulate matter (PM2.5) and cardiovascular mortality

Abstract Background Numerous studies have linked fine particulate matter (PM2.5) to increased cardiovascular mortality. Less is known how the PM2.5-cardiovascular mortality association varies by use of cardiovascular medications. This study sought to quantify effect modification by statin use status on the associations between long-term exposure to PM2.5 and mortality from any cardiovascular cause, coronary heart disease (CHD), and stroke. Methods In this nested case-control study, we followed 1.2 million community-dwelling adults aged ≥66 years who lived in Ontario, Canada from 2000 through 2018. Cases were patients who died from the three causes. Each case was individually matched to up to 30 randomly selected controls using incidence density sampling. Conditional logistic regression models were used to estimate odds ratios (ORs) for the associations between PM2.5 and mortality. We evaluated the presence of effect modification considering both multiplicative (ratio of ORs) and additive scales (the relative excess risk due to interaction, RERI). Results Exposure to PM2.5 increased the risks for cardiovascular, CHD, and stroke mortality. For all three causes of death, compared with statin users, stronger PM2.5-mortality associations were observed among non-users [e.g. for cardiovascular mortality corresponding to each interquartile range increase in PM2.5, OR = 1.042 (95% CI, 1.032–1.053) vs OR = 1.009 (95% CI, 0.996–1.022) in users, ratio of ORs = 1.033 (95% CI, 1.019–1.047), RERI = 0.039 (95% CI, 0.025–0.050)]. Among users, partially adherent users exhibited a higher risk of PM2.5-associated mortality than fully adherent users. Conclusions The associations of chronic exposure to PM2.5 with cardiovascular and CHD mortality were stronger among statin non-users compared to users.


Introduction
Ambient air pollution is a major concern globally. 1In particular, fine particulate matter ≤2.5 μm in diameter (PM 2.5 ) is a leading cause of premature mortality worldwide. 2A large burden of PM 2.5 on health is through its effect on the cardiovascular system 3 ; biological mechanisms include cardiovascular injury by aggravating oxidative stress and systemic inflammation, accelerating atherosclerosis progression, and altering cardiac autonomic function, all of which may increase cardiovascular mortality risk. 4Given the ubiquitous nature of PM 2.5 exposure and the mortality burden attributed to PM 2.5 , identifying novel strategies to complement existing air quality policies is crucial.
There has been increasing interest in heterogeneous exposure effects of PM 2.5 across different groups of individuals, to identify population subgroups who are at higher risk and would benefit more from air pollution interventions.Recently, use of cardiovascular medications has been posited as a potential effect modifier in the association between PM 2.5 and mortality, because medications with antiinflammatory and antioxidant activity were repeatedly shown to modify pathological responses to air pollution. 5or example, statins, a widely prescribed class of cholesterollowering drugs, decrease C-reactive protein and other markers of inflammatory and endothelial response. 6herefore, it is conceivable that statin use could modify the effect of PM 2.5 on inflammation and heart-rate variability. 5,6owever, epidemiological evidence as to whether cardiovascular susceptibility to air pollution differs by statin use is unclear.Several studies reported weaker associations between PM 2.5 and circulating inflammatory markers among statin users than non-users, 7-10 but two other studies reported no strong evidence of multiplicative effect modification by statins on the PM 2.5 -cardiovascular event association. 11,12Thus, whether statin non-users are at a higher risk of PM 2.5 -associated cardiovascular mortality compared to statin users remains uncertain.
The objective of this study was to evaluate whether statin use is an effect modifier in the associations of chronic PM 2.5 exposure with cardiovascular, coronary heart disease (CHD), and stroke mortality.We also sought to determine whether the effect modification varies by statin use adherence, dosage and selected individual characteristics.

Study design and population
We conducted a nested case-control study among all community-dwelling adults aged ≥66 years who resided in the Canadian province of Ontario on 1 January 2000.Ontario's residents have universal access to hospital care and physician services.Additionally, prescription drug coverage (i.e.Ontario Drug Benefit Plan, ODB) starts automatically when Ontarians reach 65 years of age.Eligible communitydwelling Ontarians (n ¼ 1 171 730, exclusion criteria in the Supplementary Material, available as Supplementary data at IJE online) were censored when reaching the end of followup (31 December 2018), becoming ineligible for provincial health insurance, or death.Due to the time-dependent nature of exposures to PM 2.5 and statin use, we applied the nested case-control design. 13We selected controls from the same population as the cases to minimize selection bias. 13

Case and control identification
Using unique encoded identifiers, we linked the study population to multiple Ontario health administrative databases and analysed them at ICES (formerly the Institute for Clinical Evaluative Sciences).We ascertained cause-specific deaths from the Office of the Registrar General Vital Statistics Death Database.We defined cases as patients who died from any cardiovascular cause, CHD, or stroke, respectively, as detailed in Supplementary Table S1, available as Supplementary data at IJE online.
We selected controls using incidence density sampling. 14riefly, for each case, we formed a risk set of all potential controls consisting of all eligible subjects who did not die at the failure time of the cases.A random sample of up to 30 controls was selected from each risk set and matched to the case at index date (i.e. the death date) to maximize power while avoiding computational constraints. 15A subject was eligible to serve as a control repeatedly prior to becoming a case.Cases and controls were also matched by baseline age and sex.

PM 2.5 exposure assessment
We derived annual PM 2.5 concentrations by integrating satellite-derived aerosol optical depth data with ground-level PM 2.5 measurements, utilizing a global atmospheric chemistry transport model.This integration was refined through the application of a geographically weighted regression model. 16ur PM 2.5 estimates were characterized by a spatial resolution near 1 km × 1 km and covered the period from 2000 to 2016.The model's efficacy was validated against 2312 fixed monitoring stations in North America, exhibiting robust performance (R 2 ¼ 0.80).Owing to the limitation of data availability (2000-2016), we applied an annual calibration technique to the PM 2.5 surfaces to align them with the study period (1997-2018), similar to previous studies (details in the Supplementary Material, available as Supplementary data at IJE online). 17,18For each year in an individual's follow-up period, we assigned estimates of concentrations of PM 2.5 to the individual's annual six-character residential postal code in that year.We calculated PM 2.5 exposure based on a 3-year rolling average, allowing for a better understanding of the long-term exposure effects of PM 2.5 . 19

Statin use
We identified statin use based on the ODB prescription claims database, which includes information on the date of prescription, daily dosage and number of days supplied for each prescription.Users were identified as subjects who were dispensed any statin medication within 1 year before index date (details in the Supplementary Material, available as Supplementary data at IJE online).We also considered statin use during different time windows (i.e. 90 days and 2 years before index date) in sensitivity analyses.We calculated daily dosing and categorized them into low-to-moderate intensity and high intensity (Supplementary Table S2, available as Supplementary data at IJE online), as done previously. 20The dose estimation in the ODB has been previously validated and found to have high accuracy (89%) in determining the daily dose of statins. 21Additionally, we characterized adherence by classifying users as fully adherent if days supplied reached 80% of days within 1 year before index date, and partially adherent otherwise. 22

Covariates
][25][26] A summary of all covariates is listed in Supplementary Table S1 (available as Supplementary data at IJE online).Individual-level covariates included comorbidities (e.g.coronary heart disease and cancer), indicators of health-seeking behaviour (e.g.history of routine periodic health examination) and health-care use (e.g.frequencies of hospitalizations and outpatient visits).To further reduce possible confounding on the statin-mortality association, we considered procedures and treatments (e.g.prior coronary bypass grafting, dialysis) and concurrent medication use (e.g.β-blockers, loop diuretics).][29] Additionally, to reduce confounding on the PM 2.5 -mortality association, we considered multiple time-varying contextual socioeconomic variables at the census division and dissemination levels, using 2001, 2006 and 2016 Canadian Census data (e.g.percentages of recent immigrants, population aged ≥15 years with less than high school education).As well, we created three time-varying geographic indicators of residence (northern/southern Ontario, urban/rural, and living in the Greater Toronto Area or not) based on participants' yearly postal code to control for possible regional differences in the outcomes and statin prescriptions.We also considered duration of statin use.

Statistical analysis
To examine the impacts of PM 2.5 on cardiovascular, CHD, and stroke mortality, we applied conditional logistic regression models.For each outcome, we first built a basic model that included PM 2.5 exposure (continuous), statin non-use (non-users vs users, with users as the reference level), and an interaction term between PM 2.5 and statin non-use (details in the Supplementary Material, available as Supplementary data at IJE online).Odds ratios (ORs) for cardiovascular, CHD and stroke mortality were calculated per interquartile range (IQR) increase in PM 2.5 (2.7 μg/m 3 ).Sequentially adjusted models were then constructed by incrementally adding selected covariates, including duration of statin use, geographic indicators of residence, neighbourhood-level variables, comorbid conditions, variables for health-seeking behaviour, health-care utilization, history of procedures and treatments, and concurrent medication use (details in Supplementary Table S3, available as Supplementary data at IJE online).
We evaluated potential effect modification by statin use status in the PM 2.5 -mortality associations.We also investigated effect modification by adherence (non-users, partially adherent users vs fully adherent users) and statin dosage (non-users, low-to-moderate intensity users vs high intensity users).Additionally, we evaluated effect modification by statin use status among selected subpopulations: females, males, and patients with or without history of statinindicated conditions (Supplementary Table S1, available as Supplementary data at IJE online).We quantified effect modification on both multiplicative (ratio of ORs) and additive scales (relative excess risks due to interaction, RERI) (details in the Supplementary Material, available as Supplementary data at IJE online). 30The confidence intervals of RERIs were estimated based on the 'MOVER' method. 31o test the robustness of our effect estimates, for each outcome, we conducted sensitivity analyses by further adjusting for an area-based measure used widely to represent health inequities in Ontario, 32 using 1-year PM 2.5 exposure, restricting the study period to 2000-2016 (when PM 2.5 data were available), and ascertaining statin use status identified 90 days and 2 years before index date.Furthermore, given that statins might be not recommended for patients with chronic liver diseases due to the concern for hepatotoxicity, 33 we conducted a sensitivity analysis by excluding subjects with prior chronic liver disease (Supplementary Table S1, available as Supplementary data at IJE online).Additionally, for cardiovascular mortality, we assessed whether the effect of PM 2.5 in the non-users may further vary according to the presence or absence of statin-indicated conditions (which may reflect their eligibility to use statins).

Participant characteristics
Among the study population of 1 171 730 eligible participants, 188 801 people died from any cardiovascular cause (16.1%) from 2000 to 2018 (Table 1), of which 98 445 deaths were attributable to CHD (52.1%) and 27 803 deaths were attributable to stroke (14.7%) (Supplementary Table S4, available as Supplementary data at IJE online).Using incidence density sampling, we matched 5 662 586, 2 952 765, and 833 974 controls for cases of cardiovascular, CHD, and stroke deaths respectively.The mean age at death from cardiovascular causes was �84 years.Compared with controls, cases were more likely to have more comorbidities, live in low-income neighbourhoods, use more healthcare services, and use more cardiovascular medications.The distributions of exposures to PM 2.5 at index date were presented in Table 1 and Supplementary Table S4 (available as Supplementary data at IJE online).

Main analysis
In the basic model comprising PM 2.5 , statin non-use (nonusers vs users), and an interaction term of PM 2.5 and statin non-use, the associations of PM 2.5 with cardiovascular, CHD and stroke mortality were negative in both statin users and nonusers (Supplementary Table S5, available as Supplementary data at IJE online).Adjustment for selected covariates strengthened the PM 2.5 -mortality associations, and the associations of PM 2.5 with all three outcomes were positive in the fully adjusted models.
Additionally, effect modification by statin use status appeared to be stronger among females than males for all three outcomes (Table 3).Furthermore, for cardiovascular and CHD mortality, effect modification was observed among those with and with no statin-indicated conditions but was only present among those with no statin-indicated conditions for stroke mortality (Supplementary Table S6, available as Supplementary data at IJE online).

Sensitivity analysis
Various sensitivity analyses demonstrated that the observed effect modification by statin use status was generally robust with ratios of ORs ranging from 1.029 to 1.037 for cardiovascular mortality, 1.017 to 1.026 for CHD mortality and 1.007 to 1.025 for stroke mortality (Supplementary Table S7, available as Supplementary data at IJE online).Additionally, the associations between PM 2.5 and cardiovascular mortality were similar in the non-users according to the presence or absence of statin-indicated conditions (ORs ¼ 1.048 and 1.036) (Supplementary Table S8, available as Supplementary data at IJE online).

Discussion
In this large, nested case-control study of �1.2 million people aged ≥66 years, PM 2.5 pollution increased cardiovascular, CHD, and stroke mortality among both users and non-users.Particularly, we found that the adverse effects of PM 2.5 were larger among non-users than users, implying that statin nonusers are more sensitive to the harmful effects of PM 2.5 on the cardiovascular system than users.This effect modification by statins was even stronger among females than males.Additionally, compared to fully adherent users, partially adherent users exhibited higher PM 2.5 -associated mortality risk.These findings underscore the importance of understanding the differences in effect modification by statin use status among certain patient groups, which may motivate the discovery and implementation of more specific air pollution interventions.
In our study, the PM 2.5 -mortality associations were negative in the minimally adjusted model, but increased and became positive with incremental adjustment for potential confounding variables.A similar pattern was observed in the Canadian Census Health and Environment Cohorts (CanCHEC). 345][36] For example, a cohort study of 2.4 million Canadian adults reported a hazard ratio of 1.22 (95% CI, 1.16-1.28)for cardiovascular death for each 10 μg/m 3 increase in PM 2.5 . 19In a recent meta-analysis, Alexeeff et al. 36 found that a 10 mg/m 3 increase in chronic exposure to PM 2.5 was associated with a 23% increased risk of CHD mortality and a 24% increased risk of stroke mortality.][39] Our study extends previous knowledge by demonstrating the effect modification by statin use on the relationship between long-term exposure to PM 2.5 and cardiovascular mortality.A handful of previous studies on short-or medium-term concentrations of air pollutants suggest that statin use may modify the cardiovascular effect of these pollutants.For example, Delfino et al. 9 found that the associations between C-reactive protein and traffic PM exposures of 5 and 9 days were stronger among those not using statins than those using statins.Similarly, Alexeeff et al. 7 found reduced effects of black carbon on markers of inflammatory and endothelial response among statin users compared with nonusers.However, a few cohort studies of long-term exposure to PM 2.5 did not observe effect modification by statin use. 11,12Of note, information on statin use was only available at baseline in these studies because the effect modification by statins was considered an exploratory analysis and thus may not correctly reflect statin use at outcome. 11,12In addition, those studies had limited statistical power.
The main strength of our study was a large and wellcharacterized cohort in Canada.With �1.2 million subjects and 19 years of follow-up, we had the statistical power to robustly assess the mortality risks for specific cardiovascular causes.This also offered a unique opportunity to explore the effect modification of PM 2.5 -related mortality risk by statin use status, even among specific subgroups.Another strength is precision of recording for prescribed statins and other drugs.The ODB prescription claims database contains comprehensive and highly accurate details of prescription a The odds ratios (ORs) and 95% confidence intervals (CIs) for cause-specific mortality risks in relation to each interquartile range change in PM 2.5 (2.7 μg/m 3 ) using conditional logistic regression models adjusting for duration of statin use, geographic indicators (e.g.urban/rural), neighbourhood-level covariates (e.g. % of recent immigrants and population with low education), comorbidities (e.g.hypertension, diabetes, lipid disorders, chronic renal failure, cancer and dementia), health-seeking behaviours (e.g.history of physical examination and influenza vaccination), health care utilization (e.g. the numbers of hospital admissions and continuity of care), procedures and treatment (e.g.coronary bypass grafting), use of other medications (e.g.β blockers, calcium channel blockers and drugs for antipsychotics).medications dispensed to Ontario residents aged ≥65 years, which allowed us to determine 'current' users of statins and consider statin intensity and adherence.An additional strength was the inclusion of various personal and socioeconomic characteristics to mitigate confounding.
This study also has limitations.First, we lacked information on individual-level risk factors such as education, ethnicity, and smoking, and were unable to eliminate the possibility of residual confounding.We attempted to address this problem by including a wide range of potential confounders that are strongly associated with these personal factors, such as comorbidities, healthcare access and utilization, concurrent medication use, and neighbourhood deprivation.While this effort was beneficial to reduce confounding, especially on the statin-mortality associations, we recognize that some of these variables (e.g.comorbidities) may have fallen on the PM 2.5mortality pathway as mediators due to their ascertainment within the same look-back window as PM 2.5 exposure.
The adjustment for comorbidities had minimal impact on the associations between PM 2.5 and cardiovascular and CHD mortality, suggesting that the resulting bias to these associations was relatively small.However, this adjustment had a somewhat larger impact on the PM 2.5 -stroke association.1][42] It is also noteworthy that our estimated PM 2.5 -mortality associations are comparable with those reported in studies that had more individual data available. 43Second, for stroke mortality, we may have a more limited statistical power due to a relatively small number of cases.Third, our study was restricted to older adults because of data availability.However, a recent cohort study of Canadian adults aged 25-89 years reported a similar association between PM 2.5 and cardiovascular mortality.a The odds ratios (ORs) and 95% confidence intervals (CIs) for cause-specific mortality risks in relation to each interquartile range change in PM 2.5 (2.7 μg/m 3 ) using conditional logistic regression models adjusting for duration of statin use, geographic indicators (e.g.urban/rural), neighbourhood-level covariates (e.g. % of recent immigrants and population with low education), comorbidities (e.g.hypertension, diabetes, lipid disorders, chronic renal failure, cancer and dementia), health-seeking behaviours (e.g.history of physical examination and influenza vaccination), health care utilization (e.g. the numbers of hospital admissions and continuity of care), procedures and treatment (e.g.coronary bypass grafting), use of other medications (e.g.β blockers, calcium channel blockers and drugs for antipsychotics).
International Journal of Epidemiology, 2024, Vol.53, No. 4 Fourth, some patients may not have taken their prescribed statins or not taken the dose prescribed, leading to misclassification.This misclassification, if non-differential, would tend to underestimate rather than overestimate the true association.Fifth, we did not consider adverse effects of statins, such as neurocognitive effects, type 2 diabetes, and drugdrug interactions in this study. 44Sixth, our PM 2.5 exposure was measured based on postal codes, which do not completely reflect personal exposure (e.g.indoor exposures, occupation-related exposures) or capture daily mobility. 45astly, our exposure data were only available for 2000-2016.Annual exposure surfaces for 1997-1999 and 2017-2018 were produced by the temporal calibration.However, our estimated associations were robust to the sensitivity analysis in which we restricted the study period to 2000-2016.

Conclusion
In this large population-based study, compared to statin users, we observed that the effects of long-term exposure to PM 2.5 on cardiovascular and CHD mortality were stronger among non-users.This effect modification by statin use status was less evident for the association with stroke mortality.Our finding suggests that interventions to reduce air pollution exposure might be more beneficial to statin non-users than users.

Table 1 .
Characteristics of cases and matched controls of the cardiovascular death cohort

PM 2.5 exposure (μg/m 3 ) e
The control group was not unique by patient ID, because an individual was eligible to act as a control at different time intervals during follow-up before becoming a case.The 3-year moving average of exposure to PM 2.5 at the index date.
a b Variables used to construct the Ontario marginalization index.c Population aged ≥15 years with under high school education.d Population aged ≥15 years without employment.e

Table 2 .
Effect modification by statin use status on the associations of PM 2.5 with deaths from all cardiovascular causes, coronary heart disease, and stroke

The association between PM 2.5 and cause-specific mortality by statin use status Measure of effect modification between PM 2.5 and statin use status On the multiplicative scale On the additive scale
19

Table 3 .
Effect modification by statin adherence status and effect modification by statin use status and sex on the associations of PM 2.5 with deaths from all cardiovascular causes, coronary heart disease, and stroke

The association between PM 2.5 and cause-specific mortality by statin adherence/statin use status Measure of effect modification between PM 2.5 and statin adherence/statin use status On the multiplicative scale On the additive scale
, fine particulate matter with a diameter of ≤2.5 μm; RERI, relative excess risks due to effect modification.